Brain atrophy occurs during normal aging and is an early feature of neurodegenerative diseases associated with impaired cognitive function and memory loss. Alzheimer's disease, Huntington's disease and other related dementias cause marked loss in cognitive function, often reducing an afflicted person to an invalid state. No cure is known for Alzheimer's disease and related dementias, and the causes of these diseases are not well understood. Moreover, pre-clinical research has not yet explored strategies to recover lost memories after substantial neuronal loss has taken place.
In eukaryotic cells, nuclear DNA wraps around a protein core consisting of histones H2A, H2B, H3, and H4 to form chromatin, with basic amino acids of the histones interacting with negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin. Histones are subject to posttranslational acetylation of the α,ε-amino groups of N-terminal lysine residues. The acetylation reaction is catalyzed by enzymes termed histone acetyl transferase (HATs). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure in a manner that facilitates transcription (e.g., by allowing transcription factors increased access to DNA). A family of enzymes termed histone deacetylases (HDACs) has been reported to reverse histone acetylation. Eleven members of the HDAC family, termed HDAC1-HDAC11, have been reported and proposed as three distinct classes: class I, comprising HDACs 1, 2, 3 and 8, class II, comprising HDACs 4, 5, 6 and 7, and class IV, comprising HDAC 11. In vivo, the acetylation state of chromatin is thought to be maintained by a dynamic balance between the activities of HATs and HDACs. Regulating histone acetylation is an integral aspect of chromatin modulation and gene regulation that plays a critical role in many biological processes including cell proliferation and differentiation (Roth et al., 2001). Recent reports have detailed the importance of histone acetylation in CNS functions such as neuronal differentiation, memory formation, drug addiction, and depression (Citrome, 2003; Johannessen and Johannessen, 2003; Tsankova et al., 2006). However, it is not clear which of the 11 histone deacetylases is responsible for the observed CNS effects. For example, it was discovered that while HDAC1 Tg mice do not show any difference in learning behavior compared to the control mice, HDAC2 Tg mice have impaired learning as evaluated by Pavlovian fear conditioning and Morris water maze tests. Thus, HDAC 2 inhibitors are believed to enhance memory and learning. (US Published Patent Application 2008/0300205) Agents that increase HDAC1 activity are believed to be neuroprotective and may serve as agents for treatment of neurological disorders, including Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis (ALS), ischemic brain damage and traumatic brain injury. (U.S. patent application Ser. No. 12/508,481 entitled: ACTIVATION OF HISTONE DEACETYLASE 1 (HDAC1) PROTECTS AGAINST DNA DAMAGE AND INCREASES NEURONAL SURVIVAL).